[1] Research Proposal: The long term objective of the proposed project is to demonstrate that the cytotoxic T-lymphocyte (CTL) response can be enhanced during the symptomatic stage of a persistent retroviral infection in an outbred species by expression of the stimulatory cytokine Il-2 at the site of antigen presentation. The CTL response contributes to controlling viral replication following initial infection and during the long asymptomatic period typical of many retroviral infections. Activation of CTLs is dependent on the presence of stimulatory cytokines, such as Il-2, at the site of antigen presentation. Other cytokines, such as Il-10, can inhibit the secretion of Il-2 and the development of a CTL response. Indeed, high levels of Il-10 have been corrected with the presence of retroviral-induced disease. The proposed project is based on the hypothesis that a change in the cytokine microenvironment during persistent retroviral infection may result in down-regulation of the CTL response and progression to clinical disease. To test this hypothesis, the relationship between the cytokine mRNA expression profile of peripheral blood lymphocytes and the CTL response will be examined in bovine leukemia virus (BLV) infected cattle. Approximately 30% of BLV-infected cattle develop a clinical condition termed persistent lymphocytosis characterized as a polyclonal expansion of the CD5+ B-lymphocyte population. CD5+ B- lymphocytes secrete a variety of immunoregulatory cytokines, including Il- 10, and are a likely source of cytokines capable of down-regulating the CTL response. The first two specific aims of the proposed project are designed to establish a correlation between the CTL response and the cytokine mRNA profile in BLV-infected cows. In specific aim 1, the CTL response in asymptomatic and persistently lymphocytotic BLV-infected cows will be quantified using transfected autologous kidney cell targets. In specific aim 2, the cytokine mRNA expression profile of peripheral blood mononuclear cell subsets from asymptomatic BLV-infected, persistently lymphocytotic BLV-infected, and uninfected cows will be determined by ribonuclease protection assay. If a correlation between the cytokine environment and the CTL response exists, the question remains whether altering the cytokine environment in vivo can change the CTL response. The third specific aim will test the hypothesis that immunization of persistently lymphocytotic BLV-infected cows with autologous cells co-expressing bovine Il-2 and BLV antigens will enhance the CTL response. If this strategy is successful, it will provide an important contribution to methods for controlling retroviral-induced disease in chronically infected individuals. [2] Candidate: The candidate is a veterinarian completing a residency in comparative pathology and is a PhD candidate. This proposal constitutes her doctoral research and will provide an excellent basis for future independent research of host-virus interactions in retroviral disease.